Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Dihydrocapsaicin attenuates oxidative stress and apoptosis in acute myocardial infarction via promoting Raf-1/ASK1 complex formation.
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Chen Yanmin, Yu Jiaying, He Hualing, Xu Wencai, Yi Binghua, Lin Xingyu, Yu Qiulu, Lin Zhonghao, Lin Jiafeng, Lin Cong, Cai Chenchen, Huang Kaiyu
Аннотация
BACKGROUND: Acute myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Dihydrocapsaicin (DHC), a natural antioxidant derived from plants, has demonstrated pharmacological effects in various diseases. However, its research in the cardiovascular field remains relatively limited.
PURPOSE: This study aimed to explore the anti-oxidative and anti-apoptotic effects of DHC on MI and its underlying mechanisms.
METHODS: The MI model was established by left coronary artery ligation. In vitro, the H9c2 cardiomyocyte injury model was established via oxygen-glucose deprivation (OGD). Myocardial injury was assessed by echocardiography, infarct size, histopathological changes, and serological testing. TUNEL assay, Annexin V/PI staining assay, DHE, DCFH-DA staining and western blot analysis were used to validate cell apoptosis and oxidative stress level. The target of DHC was investigated using immunofluorescence, biotin pull-down assays, molecular docking, molecular dynamics simulations, cellular thermal shift assays (CETSA), and drug affinity responsive target stability (DARTS). Subsequently, the molecular mechanism of the interaction between Raf-1/ASK1 complex and DHC was investigated. Moreover, Raf-1 silencing or ASK1 overexpression H9c2 cardiomyocytes were used for further validation.
RESULTS: DHC was found to exert anti-oxidative and anti-apoptotic effects, attenuating cardiac dysfunction and injury in the MI model and protecting against OGD-induced injury in H9c2 cardiomyocytes. Mechanistically, Raf-1 was identified as a direct target of DHC. The protection of DHC against superoxide production and apoptotic cell death was compromised with Raf-1 silencing. Additionally, we found that DHC enhance the interaction between Raf-1 and ASK1, inhibiting the activation of the p-ASK1/p-JNK/p-P38 signaling pathway during OGD insult. The overexpression of ASK1 abolished the above protective effects of DHC.
CONCLUSION: Our results demonstrated that DHC may serve as a promising therapeutic agent for attenuating cardiac dysfunction after MI by alleviating oxidative stress and apoptosis.
PURPOSE: This study aimed to explore the anti-oxidative and anti-apoptotic effects of DHC on MI and its underlying mechanisms.
METHODS: The MI model was established by left coronary artery ligation. In vitro, the H9c2 cardiomyocyte injury model was established via oxygen-glucose deprivation (OGD). Myocardial injury was assessed by echocardiography, infarct size, histopathological changes, and serological testing. TUNEL assay, Annexin V/PI staining assay, DHE, DCFH-DA staining and western blot analysis were used to validate cell apoptosis and oxidative stress level. The target of DHC was investigated using immunofluorescence, biotin pull-down assays, molecular docking, molecular dynamics simulations, cellular thermal shift assays (CETSA), and drug affinity responsive target stability (DARTS). Subsequently, the molecular mechanism of the interaction between Raf-1/ASK1 complex and DHC was investigated. Moreover, Raf-1 silencing or ASK1 overexpression H9c2 cardiomyocytes were used for further validation.
RESULTS: DHC was found to exert anti-oxidative and anti-apoptotic effects, attenuating cardiac dysfunction and injury in the MI model and protecting against OGD-induced injury in H9c2 cardiomyocytes. Mechanistically, Raf-1 was identified as a direct target of DHC. The protection of DHC against superoxide production and apoptotic cell death was compromised with Raf-1 silencing. Additionally, we found that DHC enhance the interaction between Raf-1 and ASK1, inhibiting the activation of the p-ASK1/p-JNK/p-P38 signaling pathway during OGD insult. The overexpression of ASK1 abolished the above protective effects of DHC.
CONCLUSION: Our results demonstrated that DHC may serve as a promising therapeutic agent for attenuating cardiac dysfunction after MI by alleviating oxidative stress and apoptosis.